The UPCI Lung Cancer SPORE Project 5 is a five year multi-detector computerized tomography (CT) screening study of 6,000 5-79 year-old at high risk for developing lung cancer defined as ever-smokers of 11 or more cigarettes per day for at least 25 years, or who, if quit, quit no more than 10 years prior to entry in the study. Baseline study activities will include; 1) collecting, processing and storing baseline questionnaire and pulmonary function data, blood, and DNA; 2) screening cohort members with multi-detector CT, both at entry and two years later; 3) following each cohort member long term; 4) ascertaining all new lung cancer occurrences in the cohort, including lung cancer cases. Detected as a result of screening; and 5) acquiring formalin fixed and paraffin embedded lung tissues (and fresh snap-frozen specimens when possible) which remain following the clinical management of lung cancer. Projecting frozen specimens when possible) which remain following the clinical management of lung cancer. Projecting conservatory from the recently published results of the Early Lung Cancer Action Project (ELCAP) study, the investigators anticipate detecting, with screening CT, between 100 and 120 early lung cancer cases. A nested case-control study will be performed in which will individually match (according to age, gender, race, and month of study entry) the 100 to 120 early CT-detected lung cancer cases with CT screen-negative control subjects (two controls per case) who remain cancer free during follow-up genetic susceptibility and biochemical biomarkers will be evaluated in relation to lung cancer risk. These will include genotype with respect to specific Phase I (CYP1A1, CYP2A6), Phase II (GTSM 1, NAT*), nucleotide excision repair (XPD, XRCC1) and p53 gene polymorphisms, gastrin releasing peptide receptor (GRPR) expression level in stored mononuclear cells, and hepatocyte growth factor (HGF) and beta-carotene serum levels. Pathologic and molecular characterization of the uniquely valuable early CT-detected large tumors will include examination of GRPR, HGF, and estrogen receptor (ERalpha and ERbeta) expression patterns. In addition. Project 5 investigators and additional SPORE collaborators will conduct a comprehensive research planning process, followed by a focused SPORE solicitation, to develop and fund a definitive molecular characterization of these lesions in comparisons to clinically apparent lung cancer and normal lung tissue using emerging state-of-the-art technologies potentially including SAGE, cDNA and tissue microarrays, and proteonomic approaches.. This proposed screening CT study will provide: 1) further validation of a promising lung cancer screening methodology; 2) a peripheral blood and lung tissue biorepository supporting genetic and molecular studies of lung cancer susceptibility factors and molecular taxonomy of early lung lesions detectable by screening CT; and 3) combined clinical, questionnaire and laboratory data to develop predictive models of CT-detected lung cancer risk in high risk populations.